EP0303545B1 - Verfahren zur Herstellung von Phenyläthanolaminotetralinen - Google Patents

Verfahren zur Herstellung von Phenyläthanolaminotetralinen Download PDF

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Publication number
EP0303545B1
EP0303545B1 EP19880402094 EP88402094A EP0303545B1 EP 0303545 B1 EP0303545 B1 EP 0303545B1 EP 19880402094 EP19880402094 EP 19880402094 EP 88402094 A EP88402094 A EP 88402094A EP 0303545 B1 EP0303545 B1 EP 0303545B1
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Prior art keywords
hydroxy
formula
group
process according
preparation
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English (en)
French (fr)
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EP0303545A2 (de
EP0303545A3 (en
Inventor
Robert Boigegrain
Roberto Cecchi
Sergio Boveri
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Elf Sanofi SA
Midy SpA
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Elf Sanofi SA
Midy SpA
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Priority claimed from FR8711497A external-priority patent/FR2619378B1/fr
Priority claimed from FR8804219A external-priority patent/FR2629453B1/fr
Priority claimed from FR8807947A external-priority patent/FR2632636B1/fr
Application filed by Elf Sanofi SA, Midy SpA filed Critical Elf Sanofi SA
Priority to AT88402094T priority Critical patent/ATE77364T1/de
Publication of EP0303545A2 publication Critical patent/EP0303545A2/de
Publication of EP0303545A3 publication Critical patent/EP0303545A3/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups

Definitions

  • the present invention relates to a process for the preparation of phenylethanolaminotetralins, more particularly by amidation of a mandelic acid with an aminotetralin and reduction, the intermediates used in this process.
  • European patent 211721 describes phenylethanolaminotetralins of formula wherein X represents hydrogen, halogen, trifluoromethyl group or lower alkyl group and R represents hydrogen; a lower alkyl group unsubstituted or substituted by a cycloalkyl group containing 3 to 7 carbon atoms, a hydroxy, lower alkoxy, carboxy or lower carbalkoxy group; a cycloalkyl group containing 3 to 7 carbon atoms; or a lower alkanoyl and their pharmaceutically acceptable salts.
  • the compounds of formula (A) and their pharmaceutically acceptable salts have advantageous pharmacological properties, the compounds having the OR substituent in position 7 of tetralin having shown a particularly pronounced lipolytic activity.
  • the products of formula (A) can be prepared in the form of diastereoisomers or optically pure stereoisomers using one or both of the starting compounds in optically active form.
  • obtaining optically active stereoisomers generally involves successive crystallizations at the level of the final product which reduce the yields and, above all, entail fairly laborious operations.
  • the amide prepared by reaction of a mandelic acid with a 2-amino-7-hydroxytetraline can be O-alkylated by a lower alkyl haloacetate with very good yields and that the product thus obtained can be reduced to prepare the corresponding O-carbalcoxymethylphenylethanolaminotetralin with an overall yield higher than that of the O-alkylation described in EP 211 721.
  • the present invention relates to a process for the preparation of phenylethanolaminotetralins of formula in which X is as defined above and R ° represents hydrogen or a methyl group substituted by a carboxy or lower carbalkoxy group, and their pharmaceutically acceptable salts, characterized in that a functional derivative of a mandelic acid of formula in which X is as defined above, with an aminotetralin of formula the mandelamine thus obtained of formula in which X is as defined above, is then subjected to a reduction for the transformation of its amido group into a methyleneamino group or else to a reaction, with a lower alkyl haloacetate in the presence of a basic condensing agent, said haloacetate being a bromo-, chloro- or iodoacetate; in this second hypothesis, the product obtained is subjected, in any order, to a reduction for the transformation of its amido group into a methyleneamino group and to a possible saponification of
  • mandelic acid there can be used chloride, anhydride, a mixed anhydride, an active ester or the free acid suitably activated, for example, with dicyclohexylcarbodiimide or with benzotriazolyl-N- hexafluorophosphate oxytris- (dimethylamino) phosphonium (BOP).
  • a mandelic acid activated with a condensing agent such as BOP is used.
  • reaction of the functional derivative of mandelic acid with the 2-amino-7-hydroxytetralin of formula III above is carried out in an organic solvent such as methylene chloride, optionally in the presence of a proton acceptor, such as triethylamine.
  • an equimolecular amount of mandelic acid, BOP and aminotetralin is used.
  • a mandelamide of formula IV is obtained in the form of a pair of diastereoisomers (RR + RS) or (SS + SR) which, by separation, gives the pure enantiomers (RR) and (RS) or (SS) and (SR).
  • an (R) -mandelic acid is used, preferably (R) -3-chloromandelic acid. Racemic 3-chloromandelic acid can also be used.
  • the aminotetralin of formula III will preferably be used in optically active form.
  • the particularly preferred aminotetralins are (R) -2-amino-7-hydroxy-1,2,3,4-tetrahydronaphthalene and (S) -2-amino-7-hydroxy-1,2,3,4-tetrahydronaphthalene .
  • Racemic 2-amino-7-hydroxy-1,2,3,4-tetrahydronaphthalene can also be used.
  • the mandelamide of formula IV can be directly subjected to reduction for the transformation of the amido group into a methyleneamino group or else it is treated with a lower alkyl haloacetate in an alkaline medium.
  • the O-alkylation reaction is carried out according to known procedures using a chloroacetate, a bromoacetate or a lower alkyl iodoacetate, bromoacetate being preferred.
  • alkaline condensing agent it is possible to use a hydroxide or a carbonate of an alkali metal, for example potassium carbonate and it can be operated in the presence of a catalyst such as potassium iodide.
  • the amide IV methyl ether (lower carbalkoxy) is isolated according to conventional techniques with very good yields.
  • the product thus obtained can be directly subjected to the reduction of the amido group into a methyleneamino group, or else it can be saponified to transform the lower carbalkoxy group into a carboxy group, free or salified, according to well known techniques.
  • the reduction of the amido group into the methyleneamino group can be carried out on a mandelamide of formula in which X and R ° are as defined above.
  • the mandelamide reduction step of formula IVa is carried out, for example, by the action of a hydride such as lithium aluminum hydride or diborane, in particular a reagent generating diborane such as the complex between borane and dimethylsulfide, hereinafter designated "borane-methylsulfide".
  • a hydride such as lithium aluminum hydride or diborane
  • a reagent generating diborane such as the complex between borane and dimethylsulfide, hereinafter designated "borane-methylsulfide”.
  • the reaction is carried out in an organic solvent, such as tetrahydrofuran and the compound of formula I is isolated according to known techniques.
  • this group can also be reduced to alcohol. It is therefore desirable, in this case, to use a reduction reagent which makes it possible to obtain, at least preferably, the selective reduction of the amide group.
  • the products of formula Ia are new and have good activity on intestinal motility.
  • the 2-amino-7-hydroxytetralin of formula III is prepared from the corresponding methoxytetralone of formula by reaction with benzylamine, reduction with sodium borohydride of the benzylimine thus obtained, debenzylation by catalytic hydrogenation and demethylation with hydrobromic acid at 48%.
  • the two optically active forms of the aminotetralins of formula III are prepared by resolution of the racemates according to known methods, for example by salification with an optically active acid, preferably mandelic acid.
  • the subject of the present invention is, according to another of its aspects, the compounds of formula IVa, in racemic form or in the form of their separate stereoisomers.
  • the hydrochloride of this product has a rotary power which corresponds to that of the literature (Molecular Pharmacology, 1982, 22, 281-289).
  • the hydrochloride of this product has a rotary power which corresponds to that of the literature (Molecular Pharmacology 1982, 22, 281-289).
  • the purified base is dissolved in 10 ml of ethyl acetate and, by cooling, 0.35 g of SR 58339 base is obtained; mp 133-138 ° C; percentage of diastereoisomers not defined.
  • the diastereoisomers (RS, SR) and (RR, SS) are not visible in chromatography and can only be separated by other techniques. Its hydrochloride, SR 58339A, is described in Example 8 of European patent 211721.
  • Example 5 According to the procedure described in Example 5 and starting from 4 g of SR 58536, obtained as described in Example 1 (c), 2.4 g of pure SR 58524, crystallized from isopropanol, is obtained; m.p. 143-145 ° C
  • Example 12 According to the procedure described in Example 12, starting from 4.7 g of SR 58533, obtained as described in Example 8 (c), a base is obtained in the form of a residual oil which is purified by flash chromatography eluting with a methylene chloride / methanol mixture 95/5. The purified base is dissolved in acetone, the solution is filtered and isopropanol saturated with hydrochloric acid is added. After filtration, it is crystallized twice from isopropanol. The product is cooled, filtered and washed first with isopropanol and then with acetone.
  • a base is obtained in the form of a residual oil which purified by flash chromatography, eluting with a methylene chloride / methanol mixture 95/5.
  • the purified base is dissolved in acetone, the solution is filtered and isopropanol saturated with hydrochloric acid is added. After filtration, it is crystallized twice from isopropanol. The product is cooled, filtered and washed first with isopropanol and then with acetone.
  • the organic phase is washed twice with 30 ml of a 2N hydrochloric acid solution and then twice with 30 ml of a saturated sodium chloride solution.
  • the organic solution is dried over sodium sulfate, filtered and evaporated to dryness.
  • the oil obtained is purified by flash chromatography using as solvent a mixture of ethyl acetate / cyclohexane 55/45.
  • a pasty solid is obtained which is taken up with 20 ml of ethyl ether in which the product crystallizes. 10 ml of cyclohexane are added, filtered, washed with a 2/1 cyclohexane / ethyl ether mixture and dried under reduced pressure at 50 ° C.
  • the aqueous phase is acidified with concentrated hydrochloric acid, extracted with ethyl acetate, the organic phase is washed with water, dried over sodium sulfate, filtered and evaporated to dryness.
  • the oil thus obtained is purified by flash chromatography using as eluent a mixture of ethyl acetate / cyclohexane 70/30.
  • the compound SR 58640 has a good activity on intestinal motility in the test of the isolated colon of rats (EP 255 415).

Claims (14)

  1. Verfahren zur Herstellung von Phenylethanolaminotetralinen der Formel
    Figure imgb0039
     worin X Wasserstoff, ein Halogen, eine Trifluormethylgruppe oder eine nied.Alkylgruppe darstellt und R° Wasserstoff oder eine durch eine Carboxygruppe oder eine nied.Carbalcoxygruppe substituierte Methylgruppe bedeutet, und deren pharmazeutisch akzeptablen Salzen, dadurch gekennzeichnet, daß man ein funktionelles Derivat einer Mandelsäure der Formel
    Figure imgb0040
     worin X wie oben definiert ist, mit einem Aminotetralin der Formel
    Figure imgb0041
     behandelt, das so erhaltene Mandelsäureamid der Formel
    Figure imgb0042
     worin X wie oben definiert ist, dann einer Reduktion zur Überführung seiner Amidogruppe in eine Methylenaminogruppe oder einer Reaktion mit einem nied.Alkylhalogenacetat in Gegenwart eines basischen Kondensationsmittels unterzieht, wobei das Halogenacetat ein Brom-, Chlor- oder Iodacetat ist, in diesem zweiten möglichen Fall das erhaltene Produkt in beliebiger Reihenfolge einer Reduktion zur Überführung seiner Amidogruppe in eine Methylenaminogruppe und gegebenenfalls einer Verseifung der nied.Carbalcoxygruppe in eine Carboxygruppe unterzieht, und gegebenenfalls das so erhaltene Produkt in eines seiner pharmazeutisch akzeptablen Salze überführt.
  2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß man als Ausgangsprodukt eine Mandelsäure in (R)-Konfiguration verwendet.
  3. Verfahren nach einem der Ansprüche 1 und 2, dadurch gekennzeichnet, daß man als Ausgangsmandelsäure (R)-3-Chlormandelsäure verwendet.
  4. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß man als Ausgangsprodukt racemische 3-Chlormandelsäure verwendet.
  5. Verfahren nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, daß man als funktionelles Derivat der Ausgangsmandelsäure die mit Benzotriazolyl-N-oxytris-(dimethylamino)-phosphonium-hexafluorphosphat aktivierte freie Säure verwendet.
  6. Verfahren nach einem der Ansprüche 1 bis 5, dadurch gekennzeichnet, daß man als Ausgangsaminotetralin racemisches 2-Amino-7-hydroxy-1,2,3,4-tetrahydronaphthalin verwendet.
  7. Verfahren nach einem der Ansprüche 1 bis 6, dadurch gekennzeichnet, daß man als Ausgangsprodukt (S)-2-Amino-7-hydroxy-1,2,3,4-tetrahydronaphthalin verwendet.
  8. Verfahren zur Herstellung eines Mandelsäureamids der Formel
    Figure imgb0043
     worin X und R° wie in Anspruch 1 definiert sind, dadurch gekennzeichnet, daß man ein funktionelles Derivat einer Mandelsäure der Formel
    Figure imgb0044
     worin X wie oben definiert ist, mit einem Aminotetralin der Formel
    Figure imgb0045
     behandelt, das so erhaltene Mandelsäureamid der Formel (IVa), worin R° Wasserstoff ist, gegebenenfalls in seine Isomeren auftrennt, und, wenn ein Mandelsäureamid der Formel (IVa), worin R° nicht Wasserstoff ist, erhalten werden soll, die so erhaltene verbindung einer Reaktion mit einem nied.Alkylhalogenacetat in Gegenwart eines basischen Mittels, wobei das Halogenacetat ein Brom-, Chlor- oder Iodacetat ist, und gegebenenfalls einer Verseifung der nied.Carbalkoxygruppe in eine Carboxygruppe unterzieht.
  9. Verfahren nach Anspruch 8 zur Herstellung des N-(7-Hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-3-chlor-mandelsäureamids.
  10. Verfahren nach Anspruch 8 zur Herstellung des (RS,SR)-N-(7-Hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-3-chlor-mandelsäureamids.
  11. Verfahren nach Anspruch 8 zur Herstellung des (RR,SS)-N-(7-Hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-3-chlor-mandelsäureamids.
  12. Verfahren nach Anspruch 8 zur Herstellung des N-[(2R)-7-Hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(R)-3-chlor-mandelsäureamids.
  13. Verfahren nach Anspruch 8 zur Herstellung des N-[(2S)-7-Hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(R)-3-chlor-mandelsäureamids.
  14. Verfahren nach Anspruch 8 zur Herstellung des N-[(2S)-7-Carbethoxymethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(R)-mandelsäureamids.
EP19880402094 1987-08-12 1988-08-11 Verfahren zur Herstellung von Phenyläthanolaminotetralinen Expired - Lifetime EP0303545B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT88402094T ATE77364T1 (de) 1987-08-12 1988-08-11 Verfahren zur herstellung von phenylaethanolaminotetralinen.

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
FR8711497 1987-08-12
FR8711497A FR2619378B1 (fr) 1987-08-12 1987-08-12 Procede pour la preparation de phenylethanolaminotetralines
FR8804219A FR2629453B1 (fr) 1988-03-30 1988-03-30 Procede pour la preparation de phenylethanolaminotetralines
FR8804219 1988-03-30
FR8807947A FR2632636B1 (fr) 1988-06-14 1988-06-14 Procede pour la preparation de phenylethanolaminotetralines
FR8807947 1988-06-14

Publications (3)

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EP0303545A2 EP0303545A2 (de) 1989-02-15
EP0303545A3 EP0303545A3 (en) 1989-05-24
EP0303545B1 true EP0303545B1 (de) 1992-06-17

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EP (1) EP0303545B1 (de)
JP (1) JP2731913B2 (de)
DE (1) DE3872100T2 (de)
ES (1) ES2045164T3 (de)
GR (1) GR3005726T3 (de)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2648042B1 (fr) * 1989-06-13 1994-06-10 Midy Spa Utilisation de phenylethanolaminotetralines pour la preparation de medicaments pour le traitement des affections oculaires
FR2653765B1 (fr) * 1989-10-31 1993-08-06 Midy Spa Procede pour la preparation enantioselective de 2-aminotetralines.
FR2656607B1 (fr) * 1989-12-29 1994-03-11 Midy Spa Phenylethanolaminomethyltetralines.
IE65511B1 (en) * 1989-12-29 1995-11-01 Sanofi Sa New phenylethanolaminomethyltetralins
FR2669821A1 (fr) * 1990-12-04 1992-06-05 Sanofi Sa Utilisation de phenylethanolaminotetralines pour la preparation de medicaments destines au traitement de la depression.
GB9107827D0 (en) * 1991-04-12 1991-05-29 Fujisawa Pharmaceutical Co New ethanolamine derivatives,processes for the preparation thereof and pharmaceutical composition comprising the same
EP2098511A1 (de) 2008-03-07 2009-09-09 Solvias AG Verfahren zur Herstellung von Verbindungen mit einer Hydronaphtalinstruktur mit einem asymmetrisch substituierten Benzolring

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2803582A1 (de) * 1978-01-27 1979-08-02 Sandoz Ag Neue tetralinderivate, ihre herstellung und verwendung
IL79323A (en) * 1985-07-10 1990-03-19 Sanofi Sa Phenylethanolaminotetralines,their preparation and pharmaceutical compositions containing them
DE3623941A1 (de) * 1986-07-16 1988-01-28 Bayer Ag Substituierte amino-5,6,7,8-tetrahydronaphthyl-oxyessigsaeuren, verfahren zu deren herstellung sowie die verwendung als arzneimittel

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EP0303545A2 (de) 1989-02-15
DE3872100D1 (de) 1992-07-23
ES2045164T3 (es) 1994-01-16
JP2731913B2 (ja) 1998-03-25
JPS6466149A (en) 1989-03-13
GR3005726T3 (de) 1993-06-07
EP0303545A3 (en) 1989-05-24
DE3872100T2 (de) 1993-01-28

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